In recent years it has been demonstrated that the growth and differentiation of eukaryotic cells is regulated by growth factors such as epidermal growth factor (EGF). Retinoids on the other hand, inhibit growth stimulatory action of EGF. Although hormone- retinoid interaction has been studied in the mammary tissues, no EGF-retinoid interaction has been investigated. In this application we propose to investigate a three way interaction between hormones, retinoids and EGF during mammary gland differentiation and carcinogenesis. Experiments will be performed to determine (1) whether EGF has a physiological role in mammary gland differentiation. Effects of EGF on the development of mammary gland, regression of the differentiated structures and formation of nodule like alveolar lesions will be evaluated in organ cultures; (2) whether mammary carcinogenesis is accompanied by gradual loss of EGF receptors. For these studies the concentration of EGF receptors and protein kinase activity will be measured in mammary tissues after carcinogen treatment of the animals; studies will also be undertaken to see if retinoid can reverse the trend; (3) whether enhancement of EGF receptor level is required for retinoid action. These studies will be conducted both in cultures and in vivo; and finally, (4) whether hormones responsible for mammary gland physiology alter EGF receptor activity in these tissues. These interactions will be studied in vivo by ovariectomizing the tumor bearing animals as well as in organ cultures by including various hormone combinations in the medium. Additional biochemical analyses including hormone receptors, retinoid binding protein, and macromolecular biosynthesis will be carried out if necessary.